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CAS No. : | 1538-08-5 | MDL No. : | MFCD00221440 |
Formula : | C2H3F3N2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OFUCCBIWEUKISP-UHFFFAOYSA-N |
M.W : | 128.05 | Pubchem ID : | 229753 |
Synonyms : |
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Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P264-P270-P301+P310-P321-P330-P405-P501 | UN#: | 2811 |
Hazard Statements: | H301 | Packing Group: | Ⅲ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With hydrazine hydrate In ethanol | Step 2 Preparation of trifluoroacetyl hydrazide A mixture of ethyl trifluoroacetate (14.2 g, 0.10 mol) and hydrazine hydrate (5.54 g, 0.11 mol) in ethanol (25 mL) was heated at reflux for 6 hours. Solvent was removed and the resulting residue was dried in vacuum to give trifluoroacetyl hydrazide (12.3 g, 96percent) as a clear oil which solidified upon standing. |
96% | With hydrazine In ethanol for 6 h; Heating / reflux | Step 2: Preparation of trifluoroacetyl hydrazide A mixture of ethyl trifluoroacetate (14.2 g, 0.10 mol) and hydrazine hydrate (5.54 g, 0.11 mol) in ethanol (25 mL) was heated at reflux for 6 hours. Solvent was removed and the resulting residue was dried in vacuum to give trifluoroacetyl hydrazide (12.3 g, 96percent) as a clear oil which solidified upon standing. |
54% | With hydrazine hydrate In ethanol for 3 h; Reflux | Ethyl trifluoroacetate (1.03 g, 0.865 mL, 7.25 mmol) and hydrazine monohydrate (80percent w/w, 0.498 g, 0.475 mL, 7.97 mmol, 1.1 equiv.) were dissolved in ethanol (1.4 mL) and heated under reflux for 3 h. The solvent was removed under reduced pressure, and the residue was taken up in EtOAc (10 mL) and extracted with water (10 mL). The aqueous phase was extracted with EtOAc (4.x.10 mL), the combined organic phases were washed with water (5 mL), dried over magnesium sulphate and freed from the solvent under reduced pressure. The residue was purified by column chromatography (SiO2, EtOAc/n-hexane 1/2, v/v). 504 mg of trifluoroacetic acid hydrazide (3.94 mmol, 54percent yield) were obtained in the form of a colourless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With hydrazine hydrate; In ethanol; | Step 2 Preparation of trifluoroacetyl hydrazide A mixture of ethyl trifluoroacetate (14.2 g, 0.10 mol) and hydrazine hydrate (5.54 g, 0.11 mol) in ethanol (25 mL) was heated at reflux for 6 hours. Solvent was removed and the resulting residue was dried in vacuum to give trifluoroacetyl hydrazide (12.3 g, 96%) as a clear oil which solidified upon standing. |
96% | With hydrazine; In ethanol; for 6h;Heating / reflux; | Step 2: Preparation of trifluoroacetyl hydrazide A mixture of ethyl trifluoroacetate (14.2 g, 0.10 mol) and hydrazine hydrate (5.54 g, 0.11 mol) in ethanol (25 mL) was heated at reflux for 6 hours. Solvent was removed and the resulting residue was dried in vacuum to give trifluoroacetyl hydrazide (12.3 g, 96%) as a clear oil which solidified upon standing. |
69.5% | With hydrazine hydrate; In acetonitrile; | Synthesis of N'-(chloroacetyl)-2,2,2-trifluoroacetohydrazide [ 60 ] (5) To a stirred solution of 60% w/v Hydrazine hydrate 2 (3.0?g (2.92?mL), 59.92?mmol, 1.0 eq.) in acetonitrile (35?mL) was added slowly ethyl trifluoroacetate 1 (8.51?g, (7.12?mL), 59.92?mmol, 1eq.) over a period of 10?min?at 10?C. The internal temperature was increased to 25 ?C from 10?C. The resulting reaction mixture was stirred at 22-25?C for 1?h. Reaction completion was checked by TLC (30% ethyl acetate: hexane). The resulting solution was cooled to 7?C. 2.4?g of 50?wt% NaOH (59.92?mmol) and chloro acetyl chloride 4 (6.77?g, (4.77?mL), 59.92?mmol) were added simultaneously over 2.5?h?at <15?C. When the reaction was monitored by TLC (30% ethyl acetate: hexane), the reaction mixture was directly distilled out to remove unwanted liquid (water and ethanol) at 27-30?C under high vacuum. During the distillation, acetonitrile (20?mL) were added slowly to maintain constant volume (10-15?mL). After the distillation, the slurry was filtered to remove NaCl and the cake was rinsed with about 2?*?5?mL of acetonitrile. The filtrate was concentrated at reduced pressure to give bishydrazide 5 product (3.0?g, 14.67?mmol, 69.5% yield, m. p. 139-140?C) which was used as such in the next step. |
54% | With hydrazine hydrate; In ethanol; for 3h;Reflux; | Ethyl trifluoroacetate (1.03 g, 0.865 mL, 7.25 mmol) and hydrazine monohydrate (80% w/w, 0.498 g, 0.475 mL, 7.97 mmol, 1.1 equiv.) were dissolved in ethanol (1.4 mL) and heated under reflux for 3 h. The solvent was removed under reduced pressure, and the residue was taken up in EtOAc (10 mL) and extracted with water (10 mL). The aqueous phase was extracted with EtOAc (4×10 mL), the combined organic phases were washed with water (5 mL), dried over magnesium sulphate and freed from the solvent under reduced pressure. The residue was purified by column chromatography (SiO2, EtOAc/n-hexane 1/2, v/v). 504 mg of trifluoroacetic acid hydrazide (3.94 mmol, 54% yield) were obtained in the form of a colourless oil. |
With hydrazine; In water; acetonitrile; at 14 - 25℃; for 2h; | INTERMEDIATE 4; 3-(Trifluoromethyl)-5,6J,8-tetrahvdrori,2,41triazolor4,3-fllpyrazine, hydrochloride salt; Step A: Bis(2,2,2-trifluoroaceto)hydrazide; Hydrazine (20.1 g, 35 wt% in water, 0.22 mol) was mixed with 310 mL of acetonitrile. 31.5 g of ethyl trifluoroacetate (0.22 mol) was added over 60 min. The internal temperature was increased to 25 C from 14 C. The resulting solution was aged at 22 - 25 C for 60 min. The solution was cooled to 7 C. 17.9 g of 50 wt% aqueous NaOH (0.22 mol) and 25.3 g of chloroacetyl chloride (0.22 mol) were added simultaneously over 130 min at a temperature below 16 C. When the reaction was complete, the mixture was vacuum distilled to remove water and ethanolat 27 ~ 30 C and under 26 ~ 27 in Hg vacuum. During the distillation, 720 mL of acetonitrile was added slowly to maintain constant volume (approximately 500 mL). The slurry was filtered to remove sodium chloride. The cake was rinsed with about 100 mL of acetonitrile. Removal of the solvent afforded the desired bishydrazide. 1H-NMR (400 MHz, DMSO-^6): 5 4.2 (s, 2H), 10.7 (s, 1H), and 11.6 (s, 1H) ppm. | |
With hydrazine; In ethanol; at 0℃; for 1.5h; | Reference Production Example 25-1 3-(trifluoromethyl)-1H-1,2,4-triazole 4.76g of hydrazine hydrate was dissolved to 160 ml of ethanol, and it was cooled to 0C. 14.21 g of ethyl 2,2,2-trifluoroacetate was dropped to it over the period of 30 minutes, followed by stirring at 0 C for 1 hour. 9.89 g of formamidine acetic acid salt was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. 200 ml of acetic acid was added to the residue, followed by stirring at 100 C for 5 hours. The reaction mixture which was cooled to room temperature was concentrated under reduced pressure. Saturated aqueous solution of sodium hydrogen carbonate was added to the residue so as to be pH 6. And then it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 5.44 g of 3-(trifluoromethyl)-1H-1,2,4-triazole. 1H-NMR(CDCl3,TMS,delta(ppm)):8.45(1H,s),12.47(1H,br.s) | |
With hydrazine hydrate; In acetonitrile; at 10 - 15℃; | Example 29: Preparation of (Z)-2,2,2-trifluoro-N'-(piperazin-2-ylidene) acetohydrazide compound of formula-40.; A solution of hydrazine hydrate (100 grams) in acetonitrile (500ml) was cooled to 10-150C and then ethyltrifluoroacetate (274 grams) was added slowly to the reaction mixture and stirred for 1.5 hours at same temperature.. After the completion of the reaction, the reaction mixture was cooled to -5 to 50C, and triethylamine (272 grams) and chloroacetyl chloride (199 grams) were added simultaneously to the reaction mixture. The reaction mixture was stirred for 3 hrs at the same temperature. After completion of the reaction, filtered the unwanted solids precipitated and washed with acetonitrile (200 ml). Distilled off the solvent form the filtrate under reduced pressure. Acetonitrile (200 ml) was added to the obtained residue at 20-30C, stirred for 15 minutes and the reaction mixture was cooled to 0-50C. Phosphorus oxytrichloride (220 ml) was added to the reaction mixture at 0-50C, slowly raised the temperature to 20-250C and then heated the reaction mixture to 80-850C. The reaction mixture was stirred for 26 hrs at same temperature and then the reaction mixture was cooled to 25-35C. The reaction mixture was added to pre 0-50C cooled aqueous methyl tertiarybutyl ether and stirred it for 45 minutes. The organic and aqueous layers were separated and aqueous layer was extracted with methyl tertiarybutyl ether. The organic layers were combined and washed with sodium bicarbonate solution followed by sodium chloride solution. Distilled off the solvent from the organic layer under reduced pressure to get 2-chloro-5-(trifluoromethyl)- 1,3,4-oxadiazole compound of formula-39. The obtained compound of formula-39 was added to the mixture of methanol (800 ml) and ethylenediamine (284 grams) at -30 to - 200C. The reaction mixture was stirred for 4 hours at the same temperature and then raised the temperature of the reaction mixture to -10 to -5C. The reaction mixture was stirred for 2 hours at -10 to -50C. The solid obtained was filtered, washed with methanol and dried to get the title compound. Yield: 100 grams | |
With hydrazine; In tetrahydrofuran; methanol; dichloromethane; | 2-5. Preparation of Trifluoroacetyl hydrazide (20) Ethyl trifluoroacetate (9.0 ml, 80.0 mmol) in methanol (8.0 mL) was stirred at 0 C. while hydrazine (90.0 ml, 0.1 mol, 1.0M solution in THF) was added. After 13 h, dichloromethane (100.0 ml) was added at room temperature and concentrated in vacuo. After evaporating the solvent, dichloromethane (60.0 ml) was added and the mixture was stirred at room temperature to product an insoluble white solid. The solid was removed and the solution was concentrated in vacuo and white gummy liquid, 20 (6.83 g, 53.3 mmol, 67%), was obtained. | |
With hydrazine hydrate; In tetrahydrofuran; at 20℃; for 12h; | Ethyl trifluoroacetate and hydrazine hydrate (1:1.2) were added in anhydrous THF (30ml) and the mixture was stirred at room temperature for 12h. The equiv of NaOH with 2-iminazole pyridine hydrochloride (1:1) were added in above-mentioned solution and heated to reflux for 12h. Sodium carbonate was used to adjust pH value. The solution was extracted into ethyl acetate, which was combined, dried over MgSO4. The residue was subjected to silica gel column chromatography using a 1:3 mixture of ethyl acetate and hexane as the eluent and crystallized in ethyl acetate. The white crystals were obtained. Yield: 80% | |
With hydrazine hydrate; In tetrahydrofuran; at 65℃; for 1h; | To tetrahydrofuran (6 mL) were added ethyl trifluoroacetate (598 mL) and hydrazine hydrate (232 mL), and themixture was stirred at 65 C for 1 hour. To the reaction solution was added Compound 4(1 g), and the mixture was stirredat 65 C for 4.5 hours. Water was added, and the mixture was extracted with ethyl acetate, washed with saturated brine,and dried over anhydrous magnesium sulfate. After the mixture was dried and concentrated under reduced pressure,the obtained solid was dissolved in ethyl acetate, activated charcoal was added, and the mixture was stirred. Subsequently,the mixture was filtered out through Celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 90:10 to 80:20) to obtainCompound 5 (1.082 g) as a white solid.MS (m/z): 292/294 [M+H]+ | |
With hydrazine hydrate; In tetrahydrofuran; at 20℃;Inert atmosphere; | b. A mixture solution of ethyl trifluoroacetate (2.0 g, 14 mmol), hydrazine hydrate (1.0 g, 21 mmol), and THF (20 mL) was stirred for 12 h at room temperature under nitrogen atmosphere. Then after NaOH (0.5 g, 14 mmol) and pyridine-2-carboximidamide hydrochloride (2.0 g, 15 mmol) were added into the mixture and heated to reflux for 12 h. After cooling to room temperature, the saturated NaHCO3 solution was added and then extracted with ethyl acetate. The organic extract was with water and dried over anhydrous MgSO4. The crude product was subjected to silica gel column chromatography using a 3:1 mixture of petroleum ether and ethyl acetate as the eluent. The white crystals of 2-(3-(trifluoromethyl)-1H-1,2,4 -triazol-5-yl)pyridine were obtained. Yield: 82 %. | |
With hydrazine; In water; acetonitrile; at 14 - 25℃; for 2h; | Hydrazine (20.1 g, 35 wt% in water, 0.22 mol) was mixed with 310 mL of acetonitrile. 31.5 g of ethyl trifluoroacetate (0.22 mol) was added over 60 min. The internal temperature was increased to 25 0C from 14 0C. The resulting solution was aged at 22 - 25 0C for 60 min. The solution was cooled to 7 0C. 17.9 g of 50 wt% aqueous NaOH (0.22 mol) and 25.3 g of chloroacetyl chloride (0.22 mol) were added simultaneously over 130 min at a temperature below 16 0C. When the reaction was complete, the mixture was vacuum distilled to remove water and ethanol at 27 ~ 30 0C and under 26 ~ 27 in Hg vacuum. During the distillation, 720 mL of acetonitrile was added slowly to maintain constant volume (approximately 500 mL). The slurry was filtered to remove sodium chloride. The cake was rinsed with about 100 mL of acetonitrile. Removal of the solvent afforded bis-hydrazide 1-1. iH-NMR (400 MHz, DMSO-et°): delta 4.2 (s, 2H), 10.7 (s, IH), and 11.6 (s, IH) ppm. 13C-NMR (100 MHz, DMSO-^6): delta 41.0, 116.1 (q, J = 362 Hz), 155.8 (q, J = 50 Hz), and 165.4 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
436 mg | In tetrahydrofuran; at 0 - 20℃; | General procedure: A portion of the catalyst (10% Pd/C(60 mg)) was added to a solution of the CBz-protected carbohydrazide 4b,c (2.0 mmol) in anhydrous THF(~50 ml). Next, the reaction flask was equipped with aseptum, a long syringe, and a balloon filled with hydrogen.Progress of the reaction was monitored by TLC (SiO2,hexane-AcOEt, 1:1), and as soon as the reaction was finished, the solution was filtered through a Celite pad.Next, the appropriate isocyanate 5a-d or isothiocyanate5e-h (2.2 mmol) was added dropwise to the filtrate whilecooling the reaction flask in an ice bath (~0C). Themixture was stirred overnight at room temperature. Afterevaporation of the solvent, the crude products were purifiedby column chromatography (SiO2, hexane, then with increasing amount (40-90%) of AcOEt in hexane). Semicarbazides 6a-f and thiosemicarbazides 6g-j were obtainedas amorphous solids by trituration with Et2O. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
405 mg | In tetrahydrofuran; at 0 - 20℃; | General procedure: A portion of the catalyst (10% Pd/C(60 mg)) was added to a solution of the CBz-protected carbohydrazide 4b,c (2.0 mmol) in anhydrous THF(~50 ml). Next, the reaction flask was equipped with aseptum, a long syringe, and a balloon filled with hydrogen.Progress of the reaction was monitored by TLC (SiO2,hexane-AcOEt, 1:1), and as soon as the reaction was finished, the solution was filtered through a Celite pad.Next, the appropriate isocyanate 5a-d or isothiocyanate5e-h (2.2 mmol) was added dropwise to the filtrate whilecooling the reaction flask in an ice bath (~0C). Themixture was stirred overnight at room temperature. Afterevaporation of the solvent, the crude products were purifiedby column chromatography (SiO2, hexane, then with increasing amount (40-90%) of AcOEt in hexane). Semicarbazides 6a-f and thiosemicarbazides 6g-j were obtainedas amorphous solids by trituration with Et2O. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
128 mg of <strong>[1538-08-5]trifluoroacetyl hydrazide</strong> was stirred in 3 ml of DMF and treated with 178 mg of thiocarbonyl diimidazole at room temperature. It was stirred for 3 hours and analyzed by LC-MS. The crude reaction mixture was then treated with 330 mg of {4-[4-(5-Amino- pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester and stirred overnight at room temperature followed by heating at 60 0C for 8 hours. The reaction was analyzed by LC- MS which indicated complete consumption of the starting material. This crude reaction mixture was treated with 100 mg of EDCI at 60 0C and stirred overnight at the same temperature. The reaction was then cooled to room temperature and diluted with water. The resulting precipitates were collected by filtration and purified by column chromatography using hepthane and ethyl acetate as its eluents to afford ((4-{4-[5-(5- trifluoromethyl-[1,3,4]oxadiazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester. The whole material was taken for the next hydrolysis step and dissolved in 4 ml of THF and water (1 :1 mixture). 80 mg of LiOH was added and the reaction was stirred at room temperature for 24 hours. LC-MS indicated the reaction was completed. The reaction mixture was then neutralized with 6N-HCI and the resulting precipitates were triturated in hepthane and ethyl acetate 1 :1 mixture and collected by filtration. The creamy filter cake was dried by air in the suction funnel to afford the title compound: 1H- NMR (400 MHz, DMSOd6, .delta ppm 1.17 (br. s., 1 H) 1.14 (d, J=12.38 Hz, 2 H) 1.49 (d, J=10.36 Hz, 3 H) 1.82 (br. s., 5 H) 2.15 (d, J=6.82 Hz, 2 H) 7.31 (d, J=8.59 Hz1 2 H) 7.92 (t. J=9.09 Hz. 3 H) 8.07 (dd, J=8.72, 2.65 Hz. 1 H) 8.67 (d. J=2.53 Hz. 1 H); LCMS (M+H)+ = 447.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrazine; In tetrahydrofuran; at 0 - 20℃; | To a solution of hydrazine (1.0 g, 31 mmol) in THF (15 mL) at 0 0C was added trifluoroacetic anhydride (6.6 g, 31 mmol) slowly with a syringe. After warming up to room temperature, the reaction mixture was concentrated to yield the desired product as white solid. LCMS calculated for C2H4F3N2O (M+H): 129.0; found: 129.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol;Heating / reflux; | The mixture of methyl 4-(pentylamino)-lH-imidazole-5-carbimidothioate (0.53 g, 2.4 mmol) and <strong>[1538-08-5]trifluoroacetic acid hydrazide</strong> (0.45 g, 3.5 mmol) in ethanol (10 mL) was refluxed overnight. The reaction mixture was concentrated to yield the product as slightly green viscous oil. LCMS calculated for C11H16F3N6 (M+H): 289.1; found: 289.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In 1,4-dioxane; butan-1-ol; at 110℃; for 5h; | A solution of 4-[p6-([tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]methoxy}-1- chloroisoquinoline (170 mg, 0.41 mmol), 2,2, 2-trifluoroacetohydrazide (0. 64 ml, 0.45 mmol) and HCl (5 mL, of 4 N in dioxane) in 1-butanol (3 mL) was heated to 110 C. After 5 h, the reaction mixture was concentrated and partitioned between saturated aqueous NaHCO3 (10 mL) and EtOAc (20 mL). The phases were separated and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified on silica gel (1: 2 hexane-ethyl acetate) to afford [6-([3-(trifluoromethyl)[1, 2, 4] triazolo [3, 4-a]isoquinolin-6- yl] oxy} methyl) pyridin-2-yl] methanol as a yellow solid: LRMS (ESI) nilz 375 (375 calcd for CisHisFsN402, M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 3 Preparation of 4-[5-(3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyridine A mixture of 3-(4'-pyridylacetyl)toluene (2.11 g, 0.01 mol) and <strong>[1538-08-5]trifluoroacetyl hydrazide</strong> (step 2) (1.0 g, 0.01 mol) was heated at 200 C. under N2 for 15 minutes. The crude residue was purified by chromatography (silica gel, 35:65 ethyl acetate/hexane) to give 4-[5-(3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyridine (0.56 g) as a white solid: m.p. 237-239 C. Anal. Calc'd for C16H12F3N3: C, 63.36; H, 3.99; N, 13.85. Found: C, 63.6; H, 4.00; N, 13.70. | ||
at 200℃; for 0.25h; | Step 3: Preparation of 4-[5-(3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyridine A mixture of 3-(4'-pyridylacetyl)toluene (2.11 g, 0.01 mol) and <strong>[1538-08-5]trifluoroacetyl hydrazide</strong> (step 2) (1.0 g, 0.01 mol) was heated at 200 C. under N2 for 15 minutes. The crude residue was purified by chromatography (silica gel, 35:65 ethyl acetate/hexane) to give 4-[5-(3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyridine (0.56 g) as a white solid: m.p. 237-239 C. Anal. Calc'd for C16H12F3N3: C, 63.36; H, 3.99; N, 13.85. Found: C, 63.6; H, 4.00; N, 13.70. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | b) Compound 23.2; To a solution of compound 23.1 (150 mg, 715 pmol) in EtOH (15. mL) was added trifluoroacetylhydrazine (101 mg, 787 pmol) and the reaction mixture was stirred at reflux for 2 h. The mixture was then concentrated under reduced pressure and the residue diluted with TFA (10 mL). The mixture was stirred at reflux for 2 h and the excess TFA was removed under reduced pressure. The mixture was diluted with EtOAc (50 mL) and successively washed with saturated aqueous NaHC03, water and brine, dried (MgS04), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (CH2Cl2:(CH3)2CO, 9:1) to afford compound 23.2 (134 mg, 59% yield) as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In water; acetonitrile; at 7 - 16℃; for 2.16667h; | INTERMEDIATE 4; 3-(Trifluoromethyl)-5,6J,8-tetrahvdrori,2,41triazolor4,3-fllpyrazine, hydrochloride salt; Step A: Bis(2,2,2-trifluoroaceto)hydrazide; Hydrazine (20.1 g, 35 wt% in water, 0.22 mol) was mixed with 310 mL of acetonitrile. 31.5 g of ethyl trifluoroacetate (0.22 mol) was added over 60 min. The internal temperature was increased to 25 C from 14 C. The resulting solution was aged at 22 - 25 C for 60 min. The solution was cooled to 7 C. 17.9 g of 50 wt% aqueous NaOH (0.22 mol) and 25.3 g of chloroacetyl chloride (0.22 mol) were added simultaneously over 130 min at a temperature below 16 C. When the reaction was complete, the mixture was vacuum distilled to remove water and ethanolat 27 ~ 30 C and under 26 ~ 27 in Hg vacuum. During the distillation, 720 mL of acetonitrile was added slowly to maintain constant volume (approximately 500 mL). The slurry was filtered to remove sodium chloride. The cake was rinsed with about 100 mL of acetonitrile. Removal of the solvent afforded the desired bishydrazide. 1H-NMR (400 MHz, DMSO-^6): 5 4.2 (s, 2H), 10.7 (s, 1H), and 11.6 (s, 1H) ppm. | |
With sodium hydroxide; In water; acetonitrile; at 7 - 16℃; | Hydrazine (20.1 g, 35 wt% in water, 0.22 mol) was mixed with 310 mL of acetonitrile. 31.5 g of ethyl trifluoroacetate (0.22 mol) was added over 60 min. The internal temperature was increased to 25 0C from 14 0C. The resulting solution was aged at 22 - 25 0C for 60 min. The solution was cooled to 7 0C. 17.9 g of 50 wt% aqueous NaOH (0.22 mol) and 25.3 g of chloroacetyl chloride (0.22 mol) were added simultaneously over 130 min at a temperature below 16 0C. When the reaction was complete, the mixture was vacuum distilled to remove water and ethanol at 27 ~ 30 0C and under 26 ~ 27 in Hg vacuum. During the distillation, 720 mL of acetonitrile was added slowly to maintain constant volume (approximately 500 mL). The slurry was filtered to remove sodium chloride. The cake was rinsed with about 100 mL of acetonitrile. Removal of the solvent afforded bis-hydrazide 1-1. iH-NMR (400 MHz, DMSO-et°): delta 4.2 (s, 2H), 10.7 (s, IH), and 11.6 (s, IH) ppm. 13C-NMR (100 MHz, DMSO-^6): delta 41.0, 116.1 (q, J = 362 Hz), 155.8 (q, J = 50 Hz), and 165.4 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 3 Preparation of 4-[5-(3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyridine A mixture of 3-(4'-pyridylacetyl)toluene (2.11 g, 0.01 mol) and <strong>[1538-08-5]trifluoroacetyl hydrazide</strong> (step 2) (1.0 g, 0.01 mol) was heated at 200 C. under N2 for 15 minutes. The crude residue was purified by chromatography (silica gel, 35:65 ethyl acetate/hexane) to give 4-[5-(3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyridine (0.56 g) as a white solid: m.p. 237-239 C. Anal. Calc'd for C16H12F3N3: C, 63.36; H, 3.99; N, 13.85. Found: C, 63.6; H, 4.00; N, 13.70. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; hydrogenchloride; In diethyl ether; water; | EXAMPLE 7 N-(4,4,4-Trinitrobutyryl)-N'-<strong>[1538-08-5](trifluoroacetyl)hydrazine</strong> (1A) To 1.65 g (0.007 mole) of 4,4,4-trinitrobutyryl chloride in 15 mL of anhydrous diethyl ether stirred in a water bath at 15 C. was added 0.9 g (0.007 mole) of <strong>[1538-08-5]N-<strong>[1538-08-5](trifluoroacetyl)hydrazine</strong></strong>. Pyridine (0.6 mL, 0.007 mole) was added dropwise. After 3 minutes, dilute hydrochloric acid was added and the ether layer was separated and dried (Na2 SO4). The volatiles were removed and the residue was stirred with water and then with CH2 Cl2 to give the product N-(4,4,4-trinitrobutyryl)-N'-<strong>[1538-08-5](trifluoroacetyl)hydrazine</strong>, 1.15 g (50%), mp 154-156 C. Crystallization from 1,2-dichloroethane raised the melting point to 157-159 C.; 1 H NMR (acetone-d6 +D2 O): 2.97 (t, 2H), 3.86 (t, 2H); IR (KBr): 3330, 3220 (NH), 1745, 1690 (C=O); 1610, 1590 (NO2); 1195 (C--F). |
Yield | Reaction Conditions | Operation in experiment |
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4.76g of hydrazine hydrate was dissolved to 160 ml of ethanol, and it was cooled to 0C. 14.21 g of ethyl 2,2,2-trifluoroacetate was dropped to it over the period of 30 minutes, followed by stirring at 0 C for 1 hour. 9.89 g of formamidine acetic acid salt was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. 200 ml of acetic acid was added to the residue, followed by stirring at 100 C for 5 hours. The reaction mixture which was cooled to room temperature was concentrated under reduced pressure. Saturated aqueous solution of sodium hydrogen carbonate was added to the residue so as to be pH 6. And then it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 5.44 g of 3-(trifluoromethyl)-1H-1,2,4-triazole. 1H-NMR(CDCl3,TMS,delta(ppm)):8.45(1H,s),12.47(1H,br.s) |
Yield | Reaction Conditions | Operation in experiment |
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Method P Preparation of 4-[3-methyl-5-(trifluoromethyl)-4H-1,2,4-triazol-4-yl]piperidine Step 1: Preparation of 1-benzyl-4-[3-methyl-5-(trifluoromethyl)-4H-1,2,4-triazol-4-yl]piperidine; Phosphorous oxychloride (13.0 ml) was added dropwise to a mixture of N-(1-benzylpiperidin-4-yl)acetamide (10.75 g) in chloroform (30 ml) containing pyridine (22.5 ml) at 0 C. under an argon atmosphere. The reaction mixture was allowed to warm to room temperature and stirring was continued for 12 hours. The reaction mixture was evaporated to dryness under vacuum and the residue was azeotroped with toluene (100 ml). The residue obtained was dissolved in chloroform (30 ml), trifluoro acetic acid hydrazide (8.89 g) was added and the mixture was heated under reflux for 4 hours. The reaction mixture was allowed to cool and saturated aqueous sodium bicarbonate (100 ml) was added and the mixture was extracted with dichloromethane (3×100 ml) and the combined extracts were dried. The residue obtained on removal of the solvent was stirred with 2M HCl (65 ml) for 2 hours. The reaction mixture was evaporated to dryness and the residue partitioned between saturated aqueous potassium carbonate (100 ml) and dichloromethane (100 ml). The aqueous portion was extracted with dichloromethane (2×100 ml), the combined organic extracts were dried and evaporated to dryness to give a brown solid, yield 2.97 g, NMR (CDCl3); 1.90 (2H, d), 2.08 (4H, m), 2.64 (3H, s), 3.04 (2H, d), 3.58 (2H, s), 4.16 (1H, m), 7.30 (5H, m). |
Yield | Reaction Conditions | Operation in experiment |
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38.3% | With mercury(II) diacetate; In N,N-dimethyl-formamide; at 80℃; | Example 10 (R)-tert-butyl 2-[4-(4-chlorobenzyl)-5-(trifluoromethyl)-4H-1,2,4-triazole-3-yl]pyrrolidine-1-carboxylate. To a mixture of thioamide from Example 2 (0.9 g, 2.5359 mmol) and <strong>[1538-08-5]2,2,2-trifluoroacetohydrazide</strong> (0.489 g, 3.8038 mmol, 1.5 eq.) in 20 mL of DMF was added mercury (II) acetate (1.212 g, 3.8038 mmol, 1.5 eq.) and the mixture was stirred at 80 C. overnight. The mixture was diluted with 40 mL of acetonitrile, filtered over a Celite-fritted funnel and washed with more acetonitrile. The filtrate was concentrated in vacuo and then diluted with EtOAc (100 mL), treated with H2O (40 mL), dried over Na2SO4, then filtered and concentrated in vacuo. Flash chromatography purification (Hex/EtOAc gradient, 10-100% EtOAc) provided the desired product (0.345 g, 38.3%). 1H NMR (300 MHz, CDCl3) delta 1.40 (s, 9H), 1.93 (m, 3H), 2.47 (m, 1H), 3.45-3.47 (m, 1H), 3.57-3.59 (m, 1H), 4.72 (m, 1H), 5.37-5.42 (d, 1H), 5.73-5.79 (d, 1H), 6.96-6.99 (d, 2H), 7.33-7.35 (d, 2H). MS: calculated: 430.85, found (MH+): 430.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | In methanol; at 70℃; for 2h; | 2,2,2-Trifluoroacetohydrazide (0.14 g, 1.0 mmol) was added to a stirred solution of ethyl 3-iodo-4-methylbenzimidate (preparation 51b, 0.30 g, 1.0 mmol) in methanol (3 mL) and the mixture was stirred and heated to 70 C. After 2 hours, the mixture was cooled and concentrated in vacuo. The residue was purified by flash chromatography (5:1 hexanes/ethyl acetate) to give the title compound (0.10 g, 27%) as a white solid. LRMS (m/z): 352 (M-1)-. 1H-NMR delta (CDCl3): 2.48 (s, 3H), 7.33 (d, J=6.0 Hz, 1H), 7.76 (dd, J=6.0 Hz and 3.0 Hz, 1H), 8.36 (d, J=3.0 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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38% | In 1-methyl-pyrrolidin-2-one; at 160℃; for 4h;Inert atmosphere; | Example 130A; 7-(2,4-Dichlorophenyl)-2-(trifluoromethyl)[1,2,4]triazolo[1,5-c]pyrimidin-5-ol 2.10 g (7.4 mmol) of ethyl [2-cyano-1-(2,4-dichlorophenyl)ethenyl]carbamate (Example 128A) and 0.95 g (7.4 mmol) of <strong>[1538-08-5]2,2,2-trifluoroacetohydrazide</strong> are dissolved in NMP (10 ml) under argon and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 160 C. for 4 h. The reaction mixture is cooled to RT, and water (20 ml) is added. Ethyl acetate (150 ml) and water (100 ml) are added, and the organic phase is separated off, dried with magnesium sulphate and concentrated. The residue is chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 4:1 to 1:1). 0.97 g (38% of theory) of the product is obtained.LCMS (method 8): Rt=1.17 min. (m/z=349 (M+H)+)1H-NMR (400 MHz, DMSO-d6): d=12.82 (br s, 1H), 7.88 (d, 1H), 7.65 (m, 2H), 7.07 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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23% | In 1-methyl-pyrrolidin-2-one; at 160℃; for 4h; | Example 131A; 2-(Trifluoromethyl)-7-[4-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-c]pyrimidin-5-ol 2.42 g (8.5 mmol) of ethyl {2-cyano-1-[4-(trifluoromethyl)phenyl]ethenyl}carbamate (Example 129A) and 1.09 g (8.5 mmol) of <strong>[1538-08-5]2,2,2-trifluoroacetohydrazide</strong> are dissolved in NMP (10 ml) and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 160 C. for 4 h. The reaction mixture is cooled to RT and ethyl acetate (150 ml) and water (100 ml) are added. The organic phase is separated off, dried with magnesium sulphate and concentrated. The residue is stirred with diethyl ether (25 ml), and the solid is filtered off and dried. 0.67 g (23% of theory) of the product is obtained.LCMS (method 3): Rt=2.29 min. (m/z=349 (M+H)+)1H-NMR (400 MHz, DMSO-d6): d=12.81 (br s, 1H), 8.05 (d, 2H), 7.95 (d, 2H), 7.37 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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Example 29: Preparation of (Z)-2,2,2-trifluoro-N'-(piperazin-2-ylidene) acetohydrazide compound of formula-40.; A solution of hydrazine hydrate (100 grams) in acetonitrile (500ml) was cooled to 10-150C and then ethyltrifluoroacetate (274 grams) was added slowly to the reaction mixture and stirred for 1.5 hours at same temperature.. After the completion of the reaction, the reaction mixture was cooled to -5 to 50C, and triethylamine (272 grams) and chloroacetyl chloride (199 grams) were added simultaneously to the reaction mixture. The reaction mixture was stirred for 3 hrs at the same temperature. After completion of the reaction, filtered the unwanted solids precipitated and washed with acetonitrile (200 ml). Distilled off the solvent form the filtrate under reduced pressure. Acetonitrile (200 ml) was added to the obtained residue at 20-30C, stirred for 15 minutes and the reaction mixture was cooled to 0-50C. Phosphorus oxytrichloride (220 ml) was added to the reaction mixture at 0-50C, slowly raised the temperature to 20-250C and then heated the reaction mixture to 80-850C. The reaction mixture was stirred for 26 hrs at same temperature and then the reaction mixture was cooled to 25-35C. The reaction mixture was added to pre 0-50C cooled aqueous methyl tertiarybutyl ether and stirred it for 45 minutes. The organic and aqueous layers were separated and aqueous layer was extracted with methyl tertiarybutyl ether. The organic layers were combined and washed with sodium bicarbonate solution followed by sodium chloride solution. Distilled off the solvent from the organic layer under reduced pressure to get 2-chloro-5-(trifluoromethyl)- 1,3,4-oxadiazole compound of formula-39. The obtained compound of formula-39 was added to the mixture of methanol (800 ml) and ethylenediamine (284 grams) at -30 to - 200C. The reaction mixture was stirred for 4 hours at the same temperature and then raised the temperature of the reaction mixture to -10 to -5C. The reaction mixture was stirred for 2 hours at -10 to -50C. The solid obtained was filtered, washed with methanol and dried to get the title compound. Yield: 100 grams |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | In xylene; at 150℃; for 0.5h;Microwave irradiation; | A solution of tert-butyl (1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1 H-pyrido[2,3-b][1 ,4]oxazin-6- yl)phenyl)cyclobutyl)carbamate (70 mg, 0.144 mmol) and <strong>[1538-08-5]2,2,2-trifluoroacetohydrazide</strong> (7.3mg, 0.057 mmol) in p-xylene (1 ml) was heated to 150C for 30 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexanes) to give the title compound (7 mg, 20%). LC S (Method D): RT = 1.633 min, M+1 = 564. NMR (500 MHz, CDCI3): 7.96 (1 H, s), 7.36-7.27 (7H, m), 7.21- 7.17 (2H, m), 5.63 (2H, s), 2.55-2.40 (4H, m), 2.14-1.98 (1 H, m), 1.88-1.78 (1 H, m), 1.37-1.20 (9H, bs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
mercury(II) diacetate; In tetrahydrofuran; at 0℃; for 2h; | A solution of compound 31 n (150 mg, 0.33 mmol) in THF (15 mL) was cooled to 0C, treated with Hg(OAc)2 (118 mg, 0.36 mmol) and CF3CONHNH2 (173 mg, 1.65 mmol), stirred for 2 h, diluted with Et20 (20 mL), filtered through Celite and evaporated. A solution of the residue in toluene/H20 (30:1 , 15 mL) was treated with TsOH H20 (250 mg, 1.32 mmol) and stirred at 75C for 12 h. The mixture was diluted with EA (30 mL) and washed with saturated K2C03. The aqueous layer was extracted with EA (20 mL). The combined organic layers were dried over Na2S04. After filtration, the filtrate was evaporated and the residue was purified by Preparative HPLC to give compound 31 as a white solid (113 mg, 64% yield). 1H NMR (500 MHz, CDCI3) delta 8.14 (d, J=7.5 Hz, 1H), 7.68 (t, J=8.5 Hz, 1 H), 7.50 (t, J=7.5 Hz, 1 H), 7.40 (d, J=8.5 Hz, 1 H), 7.15-7.10 (m, 3H), 6.76-6.70 (m, 2H), 5.71 (d, J=18.0 Hz, 1 H), 4.97 (m, 1H), 4.90 (d, J=8.0 Hz, 1 H), 4.26 (dd, J=15.0, 8.0 Hz, 1 H) 4.21 (m, 1 H), 2.59 (dd, J=13.0, 10.5 Hz, 1 H), 2.33 (dd, J=13.0, 5.0 Hz, 1 H), 2.12-1.90 (m, 2H), 1.70-1.60 (m, 2H). MS (ESI+) m/z: 535 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With NaOCH3; In methanol; ethanol; water; | 2-8. Preparation of 3-Trifluoromethyl-5-(2-pyridyl)-1,2,4-triazole (23) 2-Cyanopyridine (0.93 ml, 9.6 mmol), purchased from Aldrich, in ethanol (30.0 ml) was added to 20 (2.5 g, 19.5 mmol) and stirred at room temperature. After 30 min, 28% NaOCH3 solution in methanol (1.4 g) was added to reaction mixture and refluxed. After 2 h, ethanol was removed in vacuo and the remaining yellow gummy liquid was heated at 130 C. overnight. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and the filtrate was evaporated in vacuo. The crude product was subjected to column chromatography on silica (solvent: ethyl acetate/chloroform=1/5) and yellow solid, 23 (1.06 g, 5.0 mmol, 52%), was obtained. 1H-NMR (CDCl3) delta 8.84 (d, J=5.1 Hz, 1H), 8.35 (d, J=8.1 Hz, 1H), 8.01-7.95 (m, 1H), 7.57-7.52 (m, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With NaOCH3; In methanol; water; N,N-dimethyl-formamide; | 2-6. Preparation of 3-Trifluoromethyl-5-(4-methyl-2-pyridyl)-1,2,4-triazole (21) 2-Cyano-4-methylpyridine, 18 (1.3 g, 9.3 mmol), in N,N-dimethyl formamide (60.0 ml) was added to 20 (2.2 g, 17.2 mmol) and stirred at room temperature. After 30 min, 28% NaOCH3 solution in methanol (0.2 g) was added to the reaction mixture and refluxed at 153 C. for 2 days. The solution was evaporated in vacuo and water (50 ml) was added to the residue. This solution was extracted with ethyl acetate (50 ml*2). The organic solution was dried over sodium sulfate and the filtrate was evaporated in vacuo. The crude product was subjected to column chromatography on silica (solvent: ethyl acetate/chloroform=1/5) and white solid, 21 (0.6 g, 2.5 mmol, 27%), was obtained. 1H-NMR (CDCl3) delta 8.70 (d, 1H, J=5.4 Hz), 8.21 (s, 1H), 7.36 (s, 1H, J=5.4 Hz), 2.51 (s, 3H), 13C-NMR (CDCl3) delta 21.1, 117.2, 120.8, 123.6, 126.9, 149.1, 150.6, 155.1, HRMS (M+, 229.0703, Calcd, 229.0623). |
Yield | Reaction Conditions | Operation in experiment |
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With trifluoroacetic acid; In benzene; | Example 5 Preparation of 1,2-bis<strong>[1538-08-5](trifluoroacetyl)hydrazine</strong> Trifluoroacetic acid (7.6 mL, 0.1 mol) was added to a stirred solution of trifluoroacethydrazide (12.8 g, 0.1 mol) in benzene (100 mL) and the mixture was heated under reflux for 2 h. A Dean and Stark trap was fitted, and reflux was continued for 3 h. Reflux was continued in the absence of the Dean and Stark trap (3 h) and then with the trap refitted (20 h). The resulting white solid was collected by filtration, dried in vacuum and identified as 1,2-bis<strong>[1538-08-5](trifluoroacetyl)hydrazine</strong> (16.5 g, 73%). M.p. 173-175 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Compound i^ (128 mg, 0.515 mmol) was added to a stirred solution of trimethylorthoacetate (2.47 g, 20.6 mmol) and pyridiniump-toluenesulfonate (1.9 mg, 7.7 mumol) in EtOH (5.0 mL), and the resulting mixture was heated to 80 C. After 2 h, the reaction mixture was cooled to rt and concentrated in vacuo. Trifluoroacetic hydrazide (66.0 mg, 0.515 mmol) and acetic acid (2.0 mL) were added to the crude residue, and the resulting mixture was heated to 8OC. After 3 h, the reaction mixture was concentrated in vacuo, and the resulting crude residue was partitioned between EtOAc and satd. aq. NaHCO3. The layers were separated, and the organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (gradient elution, 0-10%MeOH/DCM as eluent) to afford the title compound, t2d. m/z (ES) 383 (MH)+ |
Yield | Reaction Conditions | Operation in experiment |
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In cyclohexanol; at 120℃; | A flask containing the title compound from Example 2 Step E (9.0 mg, 0.04 mmol), <strong>[1538-08-5]2,2,2-trifluoroacetohydrazide</strong> (3.2 mg, 0.04 mmol) and cyclohexanol (0.50 mL) was heated at 120 C overnight. The reaction was then concentrated to give a residue that was diluted with dimethylsulfoxide, acidified with trifluoroacetic acid, and passed through a syringe filter before being purified by reverse phase HPLC (CI 8 column, 10 to 100% acetonitrile/water, both 0.1% v/v trifluoroacetic acid). Fractions containing product were combined, 1 M hydrochloric acid was added, and the solution concentrated to provide the title compound: LCMS m/z 330.99 [M + H]+; 1H NMR (500 MHz, CDC13) delta 9.09 (br s, 1 H), 8.76 (br s, 1 H), 8.26 (d, J = Hz, 1 H), 7.75 - 7.59 (m, 4 H), 3.34 (br s, 1 H), 2.90 - 2.85 (m, 1 H), 2.52 - 2.40 (m, 3 H), 2.27 (br s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
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65% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | Step 1. (2R,5R)-6-(benzyloxy)-7-oxo-N'-(trifluoroacetyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (185) To solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (20 mL) were added <strong>[1538-08-5]2,2,2-trifluoroacetohydrazide</strong> 184 (0.17 g, 1.35 mmol, Aldrich), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give (2R,5R)-6-(benzyloxy)-7-oxo-N'-(trifluoroacetyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 185 (0.224 g, 65%) as a white solid. 1H NMR (400 MHz, CDCl3): delta 1.62 (1H, m), 2.01 (2H, m), 2.33 (1H, m), 2.99 (1H, d, J=12.0 Hz), 3.07 (1H, d, J=12.0 Hz), 3.34 (1H, s), 4.03 (1H, d, J=7.2 Hz), 4.90 (1H, d, J=11.2 Hz), 5.04 (1H, d, J=11.6 Hz), 7.39 (5H, m), 8.59 (1H, br s), 8.68 (1H, br s). |
65% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | To solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (20 mL) were added <strong>[1538-08-5]2,2,2-trifluoroacetohydrazide</strong> 184 (0.17 g, 1.35 mmol, Aldrich), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3- dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4- (dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give (2S,5R)-6-(benzyloxy)-7-oxo-N-(trifluoroacetyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 185 (0.224 g, 65%) as a white solid. 1H NMR (400 MHz, CDCl3): delta 1.62(1H, m), 2.01 (2H, m), 2.33 (1 H, m), 2.99 (1 H, d, J = 12.0 Hz), 3.07 (1 H, d, J = 12.0 Hz), 3.34 (1 H, s), 4.03 (1 H, d, J = 7.2 Hz ), 4.90 (1H, d, J = 11.2 Hz), 5.04 ( H, d, J = 1.6 Hz), 7.39 (5H, m), 8.59 (1 H, br s), 8.68 (1 H, br s). |
Yield | Reaction Conditions | Operation in experiment |
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1.9 g | Example 5 2-r3-r5-r5- rifluoromethylV4H-1 ,4-triazol-3-vnpyridin-2-ylV3-azaspiror5.51undecan-9- vDacetic acid Methyl 2-(3-(5-cyanopyridin-2-yl)-3-azaspiro[5.5]undecan-9-yl)acetate (29 mg, 0.089 mmol, 1.0 equiv) was charged in a vial fitted with a Teflon-lined crimp cap then 2,2,2- trifluoroacetohydrazide (110 mg, 0.859 mmol, 9.7 equiv), acetic acid (39 muEpsilon) and dioxane (350 L) were added. The vial was sealed with inclusion of air and heated at 200 C for 4 hours. The cooled mixture was directly purified by preparative reverse phase HPLC (20% to 80% acetonitrile in water with 0.05% TFA) to obtain the TFA salt of methyl 2-(3-(5-(5- (trifluoromethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-3-azaspiro[5.5]undecan-9-yl)acetate as a white solid (1.9 mg): [MH]+ calculated m/z 438; found m/z 438. The ester was dissolved in 1 mL each of THF, water and methanol. Solid lithium hydroxide hydrate (5 mg, 0.119 mmol, 35 equiv) was added and the mixture stirred at 50 C for 3 hours at which point LCMS analysis showed clean conversion to the acid. The reaction was neutralized by addition of glacial acetic acid (8 mu^) and concentrated in vacuo. The residue was dissolved in DMSO and purified by preparative reverse phase HPLC (30% to 100% acetonitrile in water with 0.05% TFA) to obtain the TFA salt of 2-(3-(5-(5-(trifluoromethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-3- azaspiro[5.5]undecan-9-yl)acetic acid as a white solid: [MH]+ calculatedd m/z 424; found m/z 424. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; for 12h;Reflux; | Ethyl trifluoroacetate and hydrazine hydrate (1:1.2) were added in anhydrous THF (30ml) and the mixture was stirred at room temperature for 12h. The equiv of NaOH with 2-iminazole pyridine hydrochloride (1:1) were added in above-mentioned solution and heated to reflux for 12h. Sodium carbonate was used to adjust pH value. The solution was extracted into ethyl acetate, which was combined, dried over MgSO4. The residue was subjected to silica gel column chromatography using a 1:3 mixture of ethyl acetate and hexane as the eluent and crystallized in ethyl acetate. The white crystals were obtained. Yield: 80%. 1H NMR (600MHz, CDCl3): delta 14.05(1H, dr), 8.84(1H, d), 8.35(1H, d), 7.99(1H, dt), 7.55(1H, ddd); FT-IR (KBr) cm-1: 3137 1606, 1494, 1461, 1428, 1217, 1189, 1009, 765, 714 | |
With sodium hydroxide; In tetrahydrofuran; for 12h;Inert atmosphere; Reflux; | b. A mixture solution of ethyl trifluoroacetate (2.0 g, 14 mmol), hydrazine hydrate (1.0 g, 21 mmol), and THF (20 mL) was stirred for 12 h at room temperature under nitrogen atmosphere. Then after NaOH (0.5 g, 14 mmol) and pyridine-2-carboximidamide hydrochloride (2.0 g, 15 mmol) were added into the mixture and heated to reflux for 12 h. After cooling to room temperature, the saturated NaHCO3 solution was added and then extracted with ethyl acetate. The organic extract was with water and dried over anhydrous MgSO4. The crude product was subjected to silica gel column chromatography using a 3:1 mixture of petroleum ether and ethyl acetate as the eluent. The white crystals of 2-(3-(trifluoromethyl)-1H-1,2,4 -triazol-5-yl)pyridine were obtained. Yield: 82 %. 1H NMR (600 MHz, CDCl3, delta): 13.40 (s, 1H), 8.82 - 8.77 (m, 1H), 8.32 (d, 1H, J = 7.9 Hz), 7.97 (t, 1H, J = 7.8 Hz), 7.53 (d, J = 7.7 Hz, 1H). FT-IR (KBr, cm-1): 3137, 1606, 1494, 1461, 1428, 1217, 1189, 1009, 765, 714. Anal. Calcd for C8H16N5F3: C, 40.17; N, 29.29; H, 6.69. Found: C, 40.55; N, 28.87; H, 7.13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With N-ethyl-N,N-diisopropylamine; In ethanol; for 5h;Reflux; | Step 1: Synthesis of (S)-tert-butyl 1-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)but-3- ynylcarbamate (22)[00277j To a stirred solution of(S)-methyl 2-(tert-butoxycarbonylamino)pent-4-ynimidothioate (17) (1 g, 4.1 mmol) and trifluoromethyl hydrazide (21) (0.634 g, 4.1 mmol) in ethanol (10 ml) was added diisopropylethyl amine (1.6 g, 12.3 mmol) and the reaction mixture was heated to reflux for 5 h. After completion of reaction, solvent was removed under reduced pressure and the crude residue was purified by column chromatography (Ethyl acetate: Hexane = 1:1) to obtain (S)-tert-butyl 1 -(3-(trifluoromethyl)- 1 H-i ,2,4-triazol-5 -yl)but-3 -ynylcarbamate (22) 14% yield. 1H NMR (400 MHz, CD3OD) (3 1.5 (s, 9H), 2.0 (s, 1H), 2.9 (d, 2H), 5.0 (d, 1H), 5.5 (d, 1H). |
14% | With N-ethyl-N,N-diisopropylamine; In ethanol; for 5h;Reflux; | To a stirred solution of (S)-methyl 2-(ri-butoxycarbonylamino)pent-4-ynimidothioate (17) (1 g, 4.1 mmol) and trifluoromethyl hydrazide (21) (0.634 g, 4.1 mmol) in ethanol (10 ml) was added diisopropylethyl amine (1.6 g, 12.3 mmol) and the reaction mixture was heated to reflux for 5 h. After completion of reaction, solvent was removed under reduced pressure and the crude residue was purified by column chromatography (Ethyl acetate: Hexane = 1 : 1 ) to obtain (S)-ierf-butyl l-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)but-3-ynylcarbamate (22) 14% yield. ]H NMR (400 MHz, CD3OD) delta 1.5 (s, 9H), 2.0 (s, 1H), 2.9 (d, 2H), 5.0 (d, 1H), 5.5 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With potassium carbonate; In ethanol; at 200℃; for 24h;Microwave irradiation; | A mixture of 50 mg 1 -(1 -ethyl-propyl)-2-thiophen-2-ylmethyl-1 H-benzoimidazole-5- carboxylic acid ((S)-1 -cyanomethyl-3-methyl-butyl)-amide, 45 mg of <strong>[1538-08-5]trifluoroacetic acid hydrazide</strong> and 4 mg of potassium carbonate in 0.6 ml of ethanol was heated to 200C in a microwave reactor for 24 h. The solvent was removed and the residue was purified by HPLC to obtain 6 mg (10%) of 1 -(1 -ethyl-propyl)-2-thiophen-2- ylmethyl-1 H-benzoimidazole-5-carboxylic acid [(S)-3-methyl-1 -(5-trifluoromethyl-1 H- [1 ,2,4]triazol-3-ylmethyl)-butyl]-amide. C27H33F3N6OS (546.66), LCMS (method 6_6_1 ): Rt = 3.14 min, m/z= 547.32 [M+H]+ |
10% | With potassium carbonate; In ethanol; at 200℃; for 24h;Microwave irradiation; | EXAMPLE 476 1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid [(S)-3-methyl-1-(5-trifluoromethyl-1H-[1,2,4]triazol-3-ylmethyl)-butyl]-amide [1894] 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid ((S)-1-cyanomethyl-3-methyl-butyl)-amide, 45 mg of <strong>[1538-08-5]trifluoroacetic acid hydrazide</strong> and 4 mg of potassium carbonate in 0.6 ml of ethanol was heated to 200 C. in a microwave reactor for 24 h. The solvent was removed and the residue was purified by HPLC to obtain 6 mg (10%) of 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid [(S)-3-methyl-1-(5-trifluoromethyl-1H-[1,2,4]triazol-3-ylmethyl)-butyl]-amide. [1896] C27H33F3N6OS (546.66), LCMS (method 6-6-1): Rt=3.14 min, m/z=547.32 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.8% | With mercury(II) diacetate; In tetrahydrofuran; at 20 - 60℃; for 2h;Cooling with ice; | To a solution of ethyl 2-thioxopiperidine-4-carboxylate (5.7 g, 14.95 mmol) in THF (203 mL) was added <strong>[1538-08-5]2,2,2-trifluoroacetohydrazide</strong> (7.8 g, 60.88 mmol) and Hg(OAc)2 (10.71 g, 33.48 mmol) at ice-water. The mixture was stirred at room temperature for 2 hours and heated at 60C for overnight, then filtered. Removed the solvent under reduced pressure and the filtrate was concentrated and purified by silica gel column chromatography (PE/EA=3/1) to afford ethyl 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylate (3.5 g, yield 43.8%). 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.10 - 1.32 (m, 3 H) 2.16 (br. s., 1 H) 2.36 (br. s, 1 H) 2.93 (br. s., 1 H) 3.02 - 3.39 (m, 2 H) 3.90 - 4.30 (m, 4 H). |
43.8% | With mercury(II) diacetate; In tetrahydrofuran; water; at 60℃; | To a solution of ethyl 2-thioxopiperidine-4-carboxylate (5.7 g, 14.95 mmol) in THF (203 mL) was added <strong>[1538-08-5]2,2,2-trifluoroacetohydrazide</strong> (7.8 g, 60.88 mmol) and Hg(OAc)2 (10.71 g, 33.48 mmol) at ice-water. The mixture was stirred at room temperature for 2 hours and heated at 60C for overnight, then filtered. Removed the solvent under reduced pressure and the filtrate was concentrated and purified by silica gel column chromatography (PE/EA=3/1) to afford ethyl 3-(trifluoromethyl)-5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyridine-7-carboxylate (3.5 g, yield 43.8%). 1H NMR (400 MHz, CHLOROFORM- ) delta ppm 1.10 - 1.32 (m, 3 H) 2.16 (br. s., 1 H) 2.36 (br. s., 1 H) 2.93 (br. s., 1 H) 3.02 - 3.39 (m, 2 H) 3.90 - 4.30 (m, 4 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.4 g | Under a nitrogen atmosphere, 7.0 g of 2,6-dicyano-4-methylpyridine was added to 30 mL of methanol, and theresultant mixture was stirred. Then, 19.5 mL of 28% methanol solution of sodium methoxide was added thereto, andthe resultant mixture was stirred at room temperature for 1 hour. Then, 5.5 mL of acetic acid was added dropwise tothis solution, and the resultant mixture was stirred for 5 minutes. Then, 17 g of trifluoroacetohydrazide was added thereto,and the resultant mixture was stirred at room temperature for 1 hour. Crystals gradually precipitated, and the crystalswere separated by filtration, and collected. To the resulting crystals, 50 mL of toluene was added, and the resultantmixture was heated and refluxed for 3 hours. After being cooled to room temperature, a crude product obtained byconcentration under reduced pressure was purified by silica gel column chromatography to obtain 6.4 g of object. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.082 g | at 65℃; for 4.5h; | To tetrahydrofuran (6 mL) were added ethyl trifluoroacetate (598 mL) and hydrazine hydrate (232 mL), and themixture was stirred at 65 C for 1 hour. To the reaction solution was added Compound 4(1 g), and the mixture was stirredat 65 C for 4.5 hours. Water was added, and the mixture was extracted with ethyl acetate, washed with saturated brine,and dried over anhydrous magnesium sulfate. After the mixture was dried and concentrated under reduced pressure,the obtained solid was dissolved in ethyl acetate, activated charcoal was added, and the mixture was stirred. Subsequently,the mixture was filtered out through Celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 90:10 to 80:20) to obtainCompound 5 (1.082 g) as a white solid.MS (m/z): 292/294 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1 : 2-[2-(trifluoroacetohydrazido)ethyl]amino}acetic acid (INT-1 ) Trifluoroacetohydrazide (2.0 mmol) and aziridine (2.0 mmol) are dissolved in diethyl ether (5 ml_) and stirred at room temperature overnight. 2-Chloroacetic acid (2.0 mmol) is added and the mixture stirred 3 h at room temperature. The precipitate is filtered and washed with diethyl ether to afford INT-1 . | ||
Step 1 : 2-[2-(trifluoroacetohydrazido)ethyl]amino}acetic acid (INT-1 ) Trifluoroacetohydrazide (2.0 mmol) and aziridine (2.0 mmol) are dissolved in diethyl ether (5 mL) and stirred at room temperature overnight. 2-Chloroacetic acid (2.0 mmol) is added and the mixture stirred 3 h at room temperature. The precipitate is filtered and washed with diethyl ether to afford INT-1 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With acetic acid; In ethanol; for 4h;Reflux; | General procedure: Indole-3-aldehyde 16 (1 mmol) and the correspondingalkyl/aryl acid hydrazide 17 (1.05 mmol) were refluxed in ethanol (5 mL) in the presence of glacial acetic acid(0.3 mL) for 4 h. On cooling the reaction mixture to roomtemperature, the crude product was precipitated, filteredand dried. Further recrystallization of the crude products inethanol allowed to obtain pure products in 85-95 % yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With acetic acid; In ethanol; for 4h;Reflux; | General procedure: Indole-3-aldehyde 16 (1 mmol) and the correspondingalkyl/aryl acid hydrazide 17 (1.05 mmol) were refluxed in ethanol (5 mL) in the presence of glacial acetic acid(0.3 mL) for 4 h. On cooling the reaction mixture to roomtemperature, the crude product was precipitated, filteredand dried. Further recrystallization of the crude products inethanol allowed to obtain pure products in 85-95 % yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With acetic acid; In ethanol; for 4h;Reflux; | General procedure: Indole-3-aldehyde 16 (1 mmol) and the correspondingalkyl/aryl acid hydrazide 17 (1.05 mmol) were refluxed in ethanol (5 mL) in the presence of glacial acetic acid(0.3 mL) for 4 h. On cooling the reaction mixture to roomtemperature, the crude product was precipitated, filteredand dried. Further recrystallization of the crude products inethanol allowed to obtain pure products in 85-95 % yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
483 mg | In tetrahydrofuran; at 0 - 20℃; | General procedure: A portion of the catalyst (10% Pd/C(60 mg)) was added to a solution of the CBz-protected carbohydrazide 4b,c (2.0 mmol) in anhydrous THF(~50 ml). Next, the reaction flask was equipped with aseptum, a long syringe, and a balloon filled with hydrogen.Progress of the reaction was monitored by TLC (SiO2,hexane-AcOEt, 1:1), and as soon as the reaction was finished, the solution was filtered through a Celite pad.Next, the appropriate isocyanate 5a-d or isothiocyanate5e-h (2.2 mmol) was added dropwise to the filtrate whilecooling the reaction flask in an ice bath (~0C). Themixture was stirred overnight at room temperature. Afterevaporation of the solvent, the crude products were purifiedby column chromatography (SiO2, hexane, then with increasing amount (40-90%) of AcOEt in hexane). Semicarbazides 6a-f and thiosemicarbazides 6g-j were obtainedas amorphous solids by trituration with Et2O. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
475 mg | In tetrahydrofuran; at 0 - 20℃; | General procedure: A portion of the catalyst (10% Pd/C(60 mg)) was added to a solution of the CBz-protected carbohydrazide 4b,c (2.0 mmol) in anhydrous THF(~50 ml). Next, the reaction flask was equipped with aseptum, a long syringe, and a balloon filled with hydrogen.Progress of the reaction was monitored by TLC (SiO2,hexane-AcOEt, 1:1), and as soon as the reaction was finished, the solution was filtered through a Celite pad.Next, the appropriate isocyanate 5a-d or isothiocyanate5e-h (2.2 mmol) was added dropwise to the filtrate whilecooling the reaction flask in an ice bath (~0C). Themixture was stirred overnight at room temperature. Afterevaporation of the solvent, the crude products were purifiedby column chromatography (SiO2, hexane, then with increasing amount (40-90%) of AcOEt in hexane). Semicarbazides 6a-f and thiosemicarbazides 6g-j were obtainedas amorphous solids by trituration with Et2O. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
471 mg | In tetrahydrofuran; at 0 - 20℃; | General procedure: A portion of the catalyst (10% Pd/C(60 mg)) was added to a solution of the CBz-protected carbohydrazide 4b,c (2.0 mmol) in anhydrous THF(~50 ml). Next, the reaction flask was equipped with aseptum, a long syringe, and a balloon filled with hydrogen.Progress of the reaction was monitored by TLC (SiO2,hexane-AcOEt, 1:1), and as soon as the reaction was finished, the solution was filtered through a Celite pad.Next, the appropriate isocyanate 5a-d or isothiocyanate5e-h (2.2 mmol) was added dropwise to the filtrate whilecooling the reaction flask in an ice bath (~0C). Themixture was stirred overnight at room temperature. Afterevaporation of the solvent, the crude products were purifiedby column chromatography (SiO2, hexane, then with increasing amount (40-90%) of AcOEt in hexane). Semicarbazides 6a-f and thiosemicarbazides 6g-j were obtainedas amorphous solids by trituration with Et2O. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
401 mg | In tetrahydrofuran; at 0 - 20℃; | General procedure: A portion of the catalyst (10% Pd/C(60 mg)) was added to a solution of the CBz-protected carbohydrazide 4b,c (2.0 mmol) in anhydrous THF(~50 ml). Next, the reaction flask was equipped with aseptum, a long syringe, and a balloon filled with hydrogen.Progress of the reaction was monitored by TLC (SiO2,hexane-AcOEt, 1:1), and as soon as the reaction was finished, the solution was filtered through a Celite pad.Next, the appropriate isocyanate 5a-d or isothiocyanate5e-h (2.2 mmol) was added dropwise to the filtrate whilecooling the reaction flask in an ice bath (~0C). Themixture was stirred overnight at room temperature. Afterevaporation of the solvent, the crude products were purifiedby column chromatography (SiO2, hexane, then with increasing amount (40-90%) of AcOEt in hexane). Semicarbazides 6a-f and thiosemicarbazides 6g-j were obtainedas amorphous solids by trituration with Et2O. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | To a stirred solution of le (0.6 g, 1.6 mmol) in dichloromethane was added N, N-diisopropylethylamine (0.8 g, 6.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.46 g, 2.4 mmol) and 1-chlorobenzotriazole (0.32 g, 2,4 mmol). After 10 minutes, trifluoroacetylhydrazide (0.25 g, 1.9 mmol) was added to the reaction solution, followed by stirring at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 8: 1) to give 0.6 g of white solid as a 76% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.029 g | With Trimethylacetic acid; at 130℃; for 1.5h; | SYNTHESIS EXAMPLE 5 Preparation of N-(2,3-difluorophenyl)-6,7-dihydro-3-(trifluoromethyl)-6-[4- (trifluoromethyl)phenyl]-5H-pyrrolo[2,1-c]-1,2,4-triazole-7-carboxamide (Compound 22) Step A: Preparation of N-(2,3-difluorophenyl)-6,7-dihydro-3-(trifluoromethyl)-6-[4- (trifluoromethyl)phenyl]-5H-pyrrolo[2,1-c]-1,2,4-triazole-7-carboxamide A mixture of N-(2,3-difluorophenyl)-3,4-dihydro-5-(methylthio)-3-[4- (trifluoromethyl)phenyl]-2H-pyrrole-4-carboxamide (i.e. the product of Example 4 Step B, 0.220 g, 0.53 mmol), <strong>[1538-08-5]trifluoroacetic hydrazide</strong> (0.076 g, 0.58 mmol) and pivalic acid (2.7 g) was stirred at 130 C for 90 min. The cooled mixture was diluted with ethyl acetate (100 mL) and washed successively with saturated sodium bicarbonate (50 mL), water (50 mL) and saturated sodium chloride (50 mL). The organic layer was dried (MgSO4), concentrated onto Celite diatomaceous earth filter aid and chromatographed on C18-silica gel, eluting with 10% to 100% 1:1 acetonitrile/methanol in water to afford the title compound contaminated with some impurities. The mixture was triturated with 1- chlorobutane to afford the title compound, a compound of the present invention, as a colorless solid (0.029 g). 1H NMR delta 9.25 (br s, 1H), 7.89 (m, 1H), 7.70 (m, 2H), 7.51 (m, 2H), 7.03 (m, 1H), 6.92 (m, 1H), 5.04 (m, 1H), 4.71 (m, 1H), 4.46 (d, J = 7.6 Hz, 1H), 4.24 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21.1 g | In benzene; at 20℃; for 12h; | A solution of p-fluorobenzaldehyde (11.2 g) 0.09 moles were dissolved in 100 ml of benzene, 11.5 g of trifluoroacetylhydrazide, 0.09 moles, Stirred at room temperature for 12 hours, To give the product trifluoroacetylhydrazone 21.1 g, 0.09 mol, Removal of the solvent, the product can be used without purification; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20 mg | In 1,2-dichloro-benzene; toluene; at 110 - 160℃; for 21h; | (5)-5-(2-chlorophenyl)-l-cyclopentyl-N-(4-(3,3-difluoropiperidin-l-yl)-l-(5- (trifluoromethyl)-4H-l,2,4-triazol-3-yl)butan-2-yl)-lH-pyrazole-3-carboxamide: A mixture of (S)-methyl 3-(5-(2-chlorophenyl)- 1-cyclopentyl- lH-pyrazole-3-carboxamido)-5-(3,3- difluoropiperidin-l-yl)pentanimidothioate (0.12 g, 0.24 mmol), trifluoro acetyl hydrazide (30 mg, 0.24 mmol) and toluene (3 ml) was heated at 110 C for 4 h. LC-MS showed little progress. Then 1,2- dichloro benzene was added, and the mixture was heated at 160 C for 17 h. It was cooled to rt, concentrated to dryness and purified to give (S)-5-(2-chlorophenyl)-l-cyclopentyl- V-(4-(3,3- difluoropiperidin- 1-yl)- 1 -(5-(trifluoromethyl)-4H- 1 ,2,4-triazol-3-yl)butan-2-yl)- lH-pyrazole-3- carboxamide (20 mg) as an off-white foam; lH NMR (200 MHz, CDC13): 51.40-2.20 (m, 14H), 2.30- 2.80 (m, 6H), 3.10-3.40 (m, 2H), 4.20-4.40 (m, 2H), 4.60-4.80 (m, IH), 6.75 (s, IH), 7.20-7.60 (m, 4H), 7.72 (d, IH, = 8.4 Hz); LC-MS (ESI): m/z calculated for C27H32CIF5N7O [M+H+]: 600 and 602, Found: 599.9 and 602.0. |
Tags: 1538-08-5 synthesis path| 1538-08-5 SDS| 1538-08-5 COA| 1538-08-5 purity| 1538-08-5 application| 1538-08-5 NMR| 1538-08-5 COA| 1538-08-5 structure
[ 815-06-5 ]
N-Methyl-2,2,2-trifluoroacetamide
Similarity: 0.66
[ 5042-30-8 ]
(2,2,2-Trifluoroethyl)hydrazine
Similarity: 0.63
[ 14719-21-2 ]
2,2,2-Trifluoro-N-(prop-2-yn-1-yl)acetamide
Similarity: 0.57
[ 815-06-5 ]
N-Methyl-2,2,2-trifluoroacetamide
Similarity: 0.66
[ 5042-30-8 ]
(2,2,2-Trifluoroethyl)hydrazine
Similarity: 0.63
[ 14719-21-2 ]
2,2,2-Trifluoro-N-(prop-2-yn-1-yl)acetamide
Similarity: 0.57
[ 815-06-5 ]
N-Methyl-2,2,2-trifluoroacetamide
Similarity: 0.66
[ 14719-21-2 ]
2,2,2-Trifluoro-N-(prop-2-yn-1-yl)acetamide
Similarity: 0.57
[ 815-06-5 ]
N-Methyl-2,2,2-trifluoroacetamide
Similarity: 0.66
[ 5042-30-8 ]
(2,2,2-Trifluoroethyl)hydrazine
Similarity: 0.63
[ 14719-21-2 ]
2,2,2-Trifluoro-N-(prop-2-yn-1-yl)acetamide
Similarity: 0.57
[ 5042-30-8 ]
(2,2,2-Trifluoroethyl)hydrazine
Similarity: 0.63
[ 815-06-5 ]
N-Methyl-2,2,2-trifluoroacetamide
Similarity: 0.66
[ 5042-30-8 ]
(2,2,2-Trifluoroethyl)hydrazine
Similarity: 0.63
[ 14719-21-2 ]
2,2,2-Trifluoro-N-(prop-2-yn-1-yl)acetamide
Similarity: 0.57
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P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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